title: BRAF V600E is a determinant of sensitivity to proteasome inhibitors.
abstract: A critical step toward defining tailored therapy in patients with cancer is the identification of genetic interactions that may impair-or boost-the efficacy of selected therapeutic approaches. Cell models able to recapitulate combinations of genetic aberrations are important to find drug-genotype interactions poorly affected by the heterogeneous genetics of human tumors. In order to identify novel pharmacogenomic relationships, we employed an isogenic cell panel that reconstructs cancer genetic scenarios. We screened a library of 43 compounds in human hTERT-HME1 epithelial cells in which PTEN or RB1 were silenced in combination with the targeted knockin of cancer-associated mutations in EGFR, KRAS, BRAF, or PIK3CA oncogenes. Statistical analysis and clustering algorithms were applied to display similar drug response profiles and mutation-specific patterns of activity. From the screen, we discovered that proteasome inhibitors show selectivity toward BRAF V600E-mutant cells, irrespective of PTEN or RB1 expression. Preferential targeting of BRAF-mutant cells by proteasome inhibitors was corroborated in a second BRAF V600E isogenic model, as well as in a panel of colorectal cancer cell lines by the use of the proteasome inhibitor carfilzomib. Notably, carfilzomib also showed striking in vivo activity in a BRAF-mutant human colorectal cancer xenograft model. Vulnerability to proteasome inhibitors is dependent on persistent BRAF signaling, because BRAF V600E blockade by PLX4720 reversed sensitivity to carfilzomib in BRAF-mutant colorectal cancer cells. Our findings indicated that proteasome inhibition might represent a valuable targeting strategy in BRAF V600E-mutant colorectal tumors.
authors.affiliation: Corresponding Authors: Federica Di Nicolantonio, Department of Oncology, University of Torino, Institute for Cancer Research and Treatment at Candiolo, Strada Provinciale 142 Km 3.95, Candiolo, I-10060, Turin, Italy. federica.dinicolantonio@unito.it.
authors.forename: Davide
authors.initials: D
authors.lastname: Zecchin
authors.forename: Valentina
authors.initials: V
authors.lastname: Boscaro
authors.forename: Enzo
authors.initials: E
authors.lastname: Medico
authors.forename: Ludovic
authors.initials: L
authors.lastname: Barault
authors.forename: Miriam
authors.initials: M
authors.lastname: Martini
authors.forename: Sabrina
authors.initials: S
authors.lastname: Arena
authors.forename: Carlotta
authors.initials: C
authors.lastname: Cancelliere
authors.forename: Alice
authors.initials: A
authors.lastname: Bartolini
authors.forename: Emily H
authors.initials: EH
authors.lastname: Crowley
authors.forename: Alberto
authors.initials: A
authors.lastname: Bardelli
authors.forename: Margherita
authors.initials: M
authors.lastname: Gallicchio
authors.forename: Federica
authors.initials: F
authors.lastname: Di Nicolantonio
mesh_terms: D048948:14-3-3 Proteins / Q000235:genetics / Q000378:metabolism; D000970:Antineoplastic Agents / Q000494:pharmacology*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D016000:Cluster Analysis; D019008:Drug Resistance, Neoplasm / Q000235:genetics*; D004354:Drug Screening Assays, Antitumor; D005095:Exoribonucleases / Q000235:genetics / Q000378:metabolism; D005260:Female; D005838:Genotype; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D009154:Mutation; D061988:Proteasome Inhibitors / Q000494:pharmacology*; D048493:Proto-Oncogene Proteins B-raf / Q000037:antagonists & inhibitors / Q000235:genetics*; D015398:Signal Transduction / Q000187:drug effects; D013449:Sulfonamides / Q000494:pharmacology; D019098:Telomerase / Q000235:genetics / Q000378:metabolism; D023041:Xenograft Model Antitumor Assays
chemical_list: D048948:14-3-3 Proteins; D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor; D007211:Indoles; C528407:PLX 4720; D061988:Proteasome Inhibitors; D013449:Sulfonamides; D048493:Proto-Oncogene Proteins B-raf; C509186:TERT protein, human; D019098:Telomerase; D005095:Exoribonucleases; C413442:SFN protein, human